PL151050B1 - Method for manufacturing new dichloraniline derivatives - Google Patents

Abstract

Compounds of the general formula (I> …<IMAGE>… [wherein… X is a bond or a C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene chain, and… Y is a bond, or a C1-4 alkylene, C2-4 alkenylene or C2-4 alkynylene chain (with the proviso that the sum total of carbon atoms in X and Y is not more than 8);… Py is a pyridyl group optionally substituted by one or two substituents selected from halogen, hydroxy, C1-3 alkyl and C1-3 alkoxy; and… R<1> and R<2> are independently hydrogen or C1-3 alkyl (with the proviso that the sum total of carbon atoms in R<1> and R<2> is not more than 4)]… and physiologically acceptable salts and solvates (e.g. hydrates) thereof,… have a stimulant action at beta 2-adreno-receptors and may be used in the treatment of diseases associated with reversible airways obstruction (such as asthma and chronic bronchitis), inflammatory and allergic skin diseases, congestive heart failure, depression, premature labour, glaucoma and gastric or peptic ulceration.

Description

PATENT DESCRIPTION

REPUBLIC

POLAND

Additional patent to patent no. - Filed: 87 02 11 / P. 264054 /

Priority: 86 02 12 UK

CZ T AND ELNIA

Ur / ędu P <jtentt> »,» i _! (>> 1 I »· · · i,

Int. Cl. ⁵ C07D 213/42

OFFICE

PATENT

RP

Application announced on: θθ io 13

Patent description published: 1990 12 31

Inventor: Lawrence Henry Charles Lunts

Patent holder: Glaxo Group Limited, London / United Kingdom /

METHOD OF MAKING NEW DERIVATIVES OF DICLOROANILINE

The subject of the invention is a process for the preparation of new dichloroaniline derivatives of the general formula I, in which X represents the group - / CH2 / 4- or - / CH2 / 2C = C-, Y represents the group -CH2-,

2

- / CH _2/2 - or - / CH2 / 3, R is hydrogen, R is hydrogen or a methyl group and Py represents a pyridyl group Sight in the 2, 3 or 4 from residue-containing molecule and optionally a substituent, such as hydroxyl or methyl as well as physiologically acceptable salts and solvates / e.g. hydrates / these compounds. These compounds stimulate adrenergic receptors / 3 ₂

The compounds of formula I have 1 or 2 asymmetric carbon atoms, namely a carbon atom in the -CH / CH / - group and a carbon atom bonded to the R- ^{* 1} · and R groups when these groups are different. It is within the scope of the invention to prepare all enantiomers and diastereoisomers and mixtures thereof, including racemates.

Compounds in which the carbon atom in the group - (CH / OH) - has the R configuration are preferred.

2

Se preferred compounds of formula 1 wherein R and R are hydrogen, X is - / CH _2/4 -, Y is -CH ₂ -, - / CH _2/2 or ^"CH 3.2> ^{d P} Y denotes an unsubstituted pyridyl group bound in position 2 or 3 to the rest of the molecule, or a pyridyl-2 group having 1 substituent, being the hydroxyl group. Among these compounds, particularly preferred are those in which Py represents an unsubstituted pyridyl group bound in position 2 the rest of the molecule.

Particularly preferred compounds are [beta] - (4'-amino-3,5-dichlorophenyl) -OCH-[6- (-2) pyridinyl-2] ethoxy _- 7-hexylaminomethyl methanol and its physiologically acceptable salts and solvates.

Suitable physiologically acceptable salts of the compounds of formula I are the salts of inorganic and organic acids, such as hydrochlorides, hydrobromides, sulfates, phosphates.

151 050

151 050 maleates, tartrates, citrates, benzoates, 4-methoxybenzoates, 2- or 4-hydroxybenzoates, 4-chlorobenzoates, benzenesulfonates, p-toluenesulfonates, methanesulfonates, naphthalenesulfonates, aminosulfonates, ascorbates, salicylates, acetates, diphenylacates , succinates, lactates, glutarates, gluconates, 1,2,3 ”propane tricarboxylates, hydroxynaphthalene carboxylates, for example 1-hydroxy or 3-hydroxynaphthalene-2 carboxylates or oleates.

The new compounds of general formula 1 are prepared by the method according to the invention, and a feature of this process is that the compound of general formula 2 in which X * is the group 2 3 3 is reduced

-CH (OH) - or the -C / = O / - group, X represents a -CH NR - group, where R is a hydrogen atom, a benzyl group, a benzyhydryl group or an oC-methylbenzyl group, or X is a -CH group = N- or -CONH-, X represents a group of the formula -CR ^A R X-, in which R, R and X are as defined above, a group of the formula -COX- in which X is as defined above or a group of pattern

-CR ^ R ^ ⁵ -, in which R ¹ and R ² are as defined above, and X ⁵ is a C.-alkenylene group or 2 Z \ 3 ** 2

C 6 -alkynylene or the group -X -X - represents a group of the formula -CH ₂ N = CR X in which R 1 and X are as defined above, X ⁴ is a group of the formula -NHR®, in which R ³ is is hydrogen, benzyl, alpha-methylbenzyl group, a diphenylmethyl group, a trójfenylo4 methyl group, an acetyl group, a trichloroacetyl or trifluoroacetyl group, or X is nitro, X * is a -Chg- - / CH _2/2 ~ » - / CH _2/3 -, Cs-Cs-alkenyl or -C Cgalkinylowę and Py * has the same meaning as Py or a group N-oksydopirydylowę, ewentual 12 3 is not substituted by a hydroxyl or methyl, wherein at least one of groups X, X, X and X ⁴ represent a reducible group and / or Y * represents a reducible group and / or Py * contains a reducible group, then any protecting group or protecting groups present is removed and the resulting compound is optionally converted change into a physiologically acceptable salt or solvate

Thus, the method for producing the most preferred compounds, i.e.- (4-amino-3,5-dichlorophenyl) -OC- {6- (2-) -pyridinyl-2 / ethoxy-hexylaminomethyl methanol and its physiologically acceptable salts and solvates is that the compound of the general formula 2, in which X ¹ is the group -CH / OH / - or, C / = O / - is reduced, X is the group of the formula -CH ⁶ NR ³ ,

2 3 wherein R represents a hydrogen atom or a benzyl group, or X is -CH = N-, X is a group - / CHG / G or -CO / CH _2/4 -, X ⁴ is a group HgN-, Y * is - / CH _2/2 -, and Py * is pyridyl or N-oksydopirydylowę, wherein at least one of X ^1, X ² and X ² is a group ulegajęcę reduction and / or Py * has an ulegajęcę reduction after which any protecting group present is removed and the resulting compound is optionally converted into a physiologically acceptable salt or solvate

The reducible groups are for X a group of the formula -C / = 0 / -, for X a group of the formula -CHgNR -, in which R is a group that can be converted into a hydrogen atom by catalytic hydrogenation, i.e. benzyl, benzhydryl or CC -methylbenzyl, a group of the formula -CH = N- and a group of the formula -CONH-, for X a group of the formula -COX- or a group of the formula -CR 5 R ⁵ - in which X ⁵ is a C 1-4 alkenylene group or C4-alkynylene, for -X ² -Χ ³ ^ a group of the formula -CH2N = CR ² X-, for X ⁴ a nitro group, for Y * a C ₂ -C ₃ -alkenylene or alkynylene group and for Py * Py group in the form of N-oxide ·

The reduction can be carried out by using reducing agents conventionally used for the reduction of ketones, imines, amides, protected amines, alkenes, alkynes, N-oxides, and nitro groups.

For example, when in formula 2 X ⁴ is nitro, it can be reduced to an amino group using hydrogen in the presence of a suitable catalyst such as platinum, platinum oxide, palladium, palladium oxide, Raney nickel or rhodium on a support such as carbon.

When χΐ in formula 2 is -C / = O / -, this group can be reduced to -CH (OH) - using hydrogen in the presence of one of the catalysts described above. Alternatively, a hydride such as boroethane or a metal hydride such as lithium aluminum hydride, sodium di (2-methoxyethoxy) aluminum hydride, sodium borohydride or aluminum hydride may also be used as the reducing agent. The reduction may be carried out in a suitable solvent

151 050 the solvent is an alcohol, e.g. methanol or ethanol, an ether such as tetrahydrofuran or a halogenated hydrocarbon such as dichloromethane

3

When X in formula 2 is a -CH ₂ NR - group or a -CH-N- group or a moiety

-X ² -X ³ - is -CH ² N-CR ² X-, then these groups may be reduced to the group -CH 2 NH, respectively. 2 and -CH 2 NHCHR X- using hydrogen in the presence of the catalyst described above. Alternatively, when

X ² or -X ² -χ3- denote the groups -CH = N- and -CH_N = CR ² X- respectively, then these groups can be.

• · ''»'·' 2 ί. 'reduced to the group -CH ₂ NH- and -CH ₂ NHCHR X- using the reducing agent and the conditions described for the reduction of the group X ¹ representing the group -C / »O / When X or X in formula 2 represent the groups -CONH- and -COX, then these groups can be reduced to groups -CH ₂ NH ₂ - and -CH ₂ X- using a hydride such as boroethane or a complexed metal hydride such as lithium aluminum hydride or sodium di (2-methoxyethoxy) aluminum hydride, in a solvent such as an ether, e.g. tetrahydrofuran or diethyl ether.

When X ³ is Cr! R ² X ⁵ / X ⁵ is C ₄ -alkenylene or C 1-6 -alkynylene / or Y * is C ₁ -C ₆ -alkenylene or C ₂ -C ₃ -alkynylene, these groups can be reduced to a group that indicates that X - / CH _2/4 - or a group that indicates that Ύ - / CH _2/2 - or - / CH _2/3 - stosujęc hydrogen in the presence of a catalyst as described above.

When Py * is a Py group in the N-oxide form it can be reduced to a Py group using hydrogen and a catalyst such as Raney nickel in a solvent such as an alcohol, e.g. methanol. _#

If it is desired to use a protected compound of formula II, it is particularly preferred to use protecting groups R ³ and / or R ⁸ which can be removed under reduction conditions, e.g. with hydrogen and a catalyst, avoiding the need for a separate deprotection step. . Suitable protecting groups are arylmethyl groups, such as benzyl, benzhydryl and o-methylbenzyl. It should be taken into account that in some reactions it may also be possible to transform the groups found on the starting materials which should be present in the products. It primarily relates to reduction processes using hydrogen and a catalyst where an unsaturated bond product is desired. It is therefore necessary to proceed with caution in accordance with known methods, using reagents which do not affect such groups, or to carry out the reaction as one of the steps in the sequence of reactions.

In the process of producing intermediates and end products, the last step of the reaction may be the removal of the protecting group. Known protecting groups can be used, for example as described in Protective Groups in Organic Chemistry, Theodora Greene, John Wiley and Sons Inc., 1981. The hydroxyl group can be protect, for example, with arylmethyl groups such as a benzyl, diphenylmethyl or triphenylmethyl group, or with acyl groups such as an acetyl group or with the formation of tetrahydropyranyl derivatives. Suitable protecting groups for the amino group are arylmethyl groups such as benzyl, o-methylbenzyl, diphenylmethyl or triphenylmethyl groups, and acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl groups.

The protecting groups can be removed by known methods. For example, arylmethyl groups can be cleaved by hydrogenolysis in the presence of a metal catalyst / e.g. palladium on carbon / · Tetrahydropyranyl groups can be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with an acid such as a mineral acid, e.g. hydrochloric acid, or a base such as sodium hydroxide or potassium carbonate, and a group such as trichloroacetyl may be removed by reduction e.g. using zinc and acetic acid.

The compounds of formula I can be obtained in the form of salts, preferably physiologically acceptable salts. If desired, such salts can be converted into the corresponding free bases following known procedures.

Physiologically acceptable salts of compounds of formula 1 can be prepared by treating a compound of formula 1 with an appropriate acid in the presence of a suitable solvent such as acetonitrile, acetone, chloroform, ethyl acetate or an alcohol, e.g. methanol, ethanol or isopropanol.

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Physiologically acceptable salts can also be prepared from other salts of the compounds of the formula I, including other physiologically acceptable salts, by following known methods.

When a specific enantiomer of a compound of formula 1 is desired, it can be obtained by resolving the corresponding racemate of a compound of formula 1 in a known manner. Thus, e.g., a suitable optically active acid can be used to form the racemate salts of the compound of formula 1. separation, for example, by fractional crystallization into diastereomeric salts, from which the desired enantiomer of the compound of formula I can be isolated by converting the salt to the desired free base.

Alternatively, the enantiomers of a compound of Formula 1 may be obtained by using appropriate optically active starting compounds and intermediates in the above-described methods.

Certain diastereoisomers of the compounds of the formula I can be obtained in a known manner by carrying out the process of the invention with the appropriate asymmetric starting compounds or by converting the isomer mixture of the compound of the formula I into the corresponding diastereomeric derivatives, e.g. salts, and then separating them in a known manner, e.g. by fractional crystallization

The compounds of formula II used in the process according to the invention are novel compounds. They can be prepared in a number of ways analogous to those set out in British Patent No. 2,165,542A. Thus, for example, the compounds of formula II in which X ¹ is -C (aO) - can be prepared by reacting a halogen ketone of formula III in which X ⁴ is as defined in formula 2, and g

Hal is a halogen atom, e.g. bromine, with an amine of formula IV wherein R is hydrogen or a group that can be converted into a hydrogen atom by catalytic hydrogenation. The reaction can be carried out in a cold or hot solvent such as tetrahydrofuran, tert-butyl methyl ether, dioxane, chloroform, dichloromethane, dimethylformamide, acetonitrile, butanone, methyl isobutyl ketone or ethyl acetate, preferably in the presence of a base such as sodium diisopropylethylamine or carbonate, another acid acceptor, such as propylene oxide.

Compounds of formula II in which X ¹ is -C / = O / - can be reduced to the corresponding compounds in which X 1 is -CH / OH / - using, for example, a metal hydride such as sodium borohydride in a solvent such as, for example, ethanol, methanol and / or tetrahydrofuran.

The amines of the formula IV, in particular those in which R and R are hydrogen, and their acid addition salts are novel compounds.

Compounds of formula II in which X is the group -CH = N- can be prepared by reacting a glyoxal derivative of formula 5, in which X is as defined in formula 2, with an amine of formula g

4, wherein R is a hydrogen atom in a solvent such as benzene, tetrahydrofuran or an alcohol, e.g. ethanol, at a temperature up to the reflux temperature of the solvent.

Compounds of formula II in which X is -COX- can be prepared by acylation of the amine of formula 6, where X ¹ and X ⁴ are as defined above and R ³ is hydrogen using an activated derivative of the acid of formula 7. Suitable the activated derivative is an imidazolide, prepared by reacting the acid of formula 7.1 with 1.1, 1 * -carbonyldiimidazole. The acylation can be performed in a solvent such as acetonitrile.

Compounds of formula II, in which X ³ is a group of formula -CR ^^ ⁵ -, in which X ⁵ is a C 1-6 alkenylene chain and / or Y * is a C ₂ -C ₃ -alkenylene or alkynylene chain, can be prepared by methods analogous to the methods for the preparation of compounds of formula 1 described above. g

The amines of formula 4, in which R is a group that can be converted into a hydrogen atom, and R ¹ and R ² are hydrogen, can be prepared by reacting a compound of formula 8, in which R 2 is hydrogen, with an amine of the formula R NH 2 The reaction can be carried out in the absence of a solvent or in the presence of a solvent such as a ketone, e.g. butanone or methyl isobutyl ketone, an ether, e.g. tetrahydrofuran or a substituted amide, e.g. dimethylformamide, optionally in the presence of a base such as sodium carbonate or an organic amine, e.g. triethylamine or N, N-diisopropylethylamine at 0 ° C to the reflux temperature of the solvent. When the reaction is carried out in the absence of a solvent, both reactants may be heated to temperatures up to, for example, 150 ° C. If necessary, the reaction is then carried out with hydrogen in the presence of a metal such as platinum as a catalyst, in which it dissolves

such as an alcohol, e.g. ethanol, to give a compound of the formula 4 where R is hydrogen

The compounds of formulas 3, 5 and 6 are known or can be prepared by methods analogous to the methods for the preparation of known compounds

Suitable methods for preparing compounds of the formulas 8, 4 and 7 are given in British Patent Nos. 2,140,800A, 2,159,151A and 2,165,542A and in the examples below.

The compounds according to the invention have a β) ₂ * ° adrenergic stimulating effect with a particularly advantageous profile. The activity of these compounds was found in tests carried out on an isolated guinea pig trachea. The tested compounds induced relaxation of contractions caused by PGF ₂ O ^ or electrical stimulation.

In these tests, the compounds according to the invention showed a particularly long duration of action.

The compounds according to the invention can be used in the treatment of diseases associated with reversible airway obstruction, such as asthma and chronic bronchitis.

These compounds are also useful in the treatment of inflammation and allergies of the skin, right ventricular circulatory failure, depression and glaucoma, and they are also useful in preterm labor and in the treatment of conditions with an indication of reduced gastric acidity, especially gastric and digestive ulcer

Thus, the compounds of the formula I and their physiologically acceptable salts and solvates can be used in the treatment or prophylaxis of diseases associated with reversible airway obstruction in humans and animals.

The compounds according to the invention may be formulated as pharmaceutical compositions for administration in any convenient way. These compositions contain at least one compound of formula I or a physiologically acceptable salt or solvate thereof as active ingredient, physiologically acceptable carriers or excipients and optionally additional therapeutic ingredients.

these agents may be in the form of formulations suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) administration, or rectal administration, administration by inhalation or insufflation being preferred.

For human treatment, the proposed daily dose of the active ingredient is 0.005 - 100 mg and can be administered in one single dose or divided into two doses.

The pharmacological activity of representative compounds according to the invention was tested in the following test:

The activity of compounds of formula I as stimulators of the β-adrenergic receptors was determined by their ability to induce contraction relaxation induced by electrical stimulation in a tape cut from a guinea pig trachea (R.A. Coleman et al., Br. □ • Pharmac ·, 1986, 88, pp. 408 - 409 / · Reference compound was isoprenaline · The potency of the compounds was expressed as the concentrations at which the effect is equal, assuming that for isoprenaline it is 1 · The results are presented in the table.

Blackboard

The relationship of example no 1 The power of action 1 1 --- - - | XX 1 0.52 XXI 1 0.07 XXII 1 0.17 Xxiii 1 1 0.4 Xxiv 1 0.24 Xxv 1 -.--- 1 -.-. 1.4

The toxicity of the compounds of formula 1 was tested on the example of the compounds of Examples XX and XXI. In the test involving the administration of the compounds in the form of an aerosol to conscious mice, no

151,050 no adverse effects were found at doses up to 5 mg / ml.

The invention is illustrated by the following examples. Examples 1-19 illustrate the production of starting and intermediate compounds, and examples XX-XLIII illustrate the process according to the invention.

In the operations described in the examples, the solutions are dried over magnesium sulphate or sodium sulphate, unless otherwise indicated. Thin Layer Chromatography (TLC) is carried out by • tO6. SiO _2. Flash column chromatography / FCC / is carried out using silica / Merck / / g 385 / and, unless otherwise stated, one of the following solvent systems: A / toluene-ethanol-0.88 ammonia, B / hexane-ethyl acetate-triethylamine, C / toluene-ethanol-triethylamine · The abbreviations used have the following meanings: THF - tetrahydrofuran, DMF - dimethylformamide, 8TPC - bis / triphenylphosphine / palladium / II / chloride, DEA - N, N-diisopropylethylamine, DMSO - dimethylsulfoxide, TAB - tetra-n-butylammonium bisulfate, mp melting point

Example I N- {6- / ^- 3- (Pyridinyl-2 / -propyn-2-yloxy) / hexyl J benzylamine · A mixture of 2.0 g 2-bromopyridine, 3.2 g N- / 6- / propyne- 2-yloxy / hexyl-benzylamine, 0.007 g of 8TPC, 0.007 g of cuprous iodide and 20 ml of diethylamine are stirred under nitrogen for 18 hours, mixed with 50 ml of aqueous sodium hydrogen carbonate solution and extracted with ethyl ether (2x100 ml). After drying the extract evaporate and the residue is purified by FCC using ethyl acetate as slusnt to give 3.0 g of the title compound as a yellow oil. TLC / ethyl ether / Rf 0.05

Example II · / Z / -2- / 4- (6-Bromohexyloxy) buten-1-yl-7-3-benzyloxypyridine. 2.74 g of / E / Z / -4- / 3-benzyloxypyridinyl-2 / buten-3-olu-1 and 10.03 g of 1,6-dibromohekean are used. The reaction takes 18 hours and extraction is ethyl acetate is used.

After purification of the product by FCC using cyclohexane-ethyl acetate (100: 0 + 95: 5) as eluent, 1.74 g of the title compound was obtained as a yellow oil. TLC / ethyl acetate cyclohexane, 5:95 (Rf * 0.17).

Example III. N- {6- / 2- / Pyridinyl-2 / ethoxy ./-hexylJ benzylamine ·

Under nitrogen, 6.3 g of 2- (2- (6-bromohexyloxy) ethyl) pyridine are added to 20 ml of benzylamine at 14O ° C. After 1 hour at 14O ° C, the mixture is cooled and partitioned between 100 ml 2M sodium hydroxide solution and 100 ml of ether. The organic layer was washed with water and brine, dried, and concentrated to a yellow oil. The excess benzylamine was distilled off under reduced pressure to leave 6.8 g of the title compound as a yellow oil. TLC / system A, 80: 20: 2 (Rf &lt; 0.44).

Example IV. N- {6- / 4- / 3-HYDROXYPRIDINYL-2 / butoxy / J hexyl benzylamine · using 1 g of 2- / ^- 4/6-bromoheksyloksy / butyl / -3-hydroxypyridine and 3 ml of benzylamine · The reaction mixture was partitioned 4 hours later, between 10 ml of 8% sodium bicarbonate solution and 10 ml of ethyl acetate. The product was purified by FCC using the C (95: 5: 1) system as eluent to give 0.8 g of the title compound as yellow oil. TLC / system C, 95: 5: 1 /

R f b 0.25.

Example V .o6- (4-amino-3,5-dichlorophenyl) -OQ- (N-benzyl-N-f6-) (2- (pyridinyl-2) / ethoxyl / hakeyl} amino-methyl-3 / methanol. Solution 1 .0 g of 1-keto-1- (4-amino-3,5-dichlorophanyl) -2-bromoethane, 1.01 g of N- β- (2- (pyridinyl-2- (ethoxy) -hexyl) benzylamine and 460 mg of OEA in 10 ml of THF is allowed to stand at room temperature for 2 hours. The precipitate formed is filtered off, the solvent is evaporated off in vacuo, the residue is mixed with 10 ml of methanol and cooled in an ice bath, and then 300 mg of sodium borohydride are added in portions under nitrogen atmosphere. After 30 minutes, the solution was brought to room temperature, stirred for 30 minutes and then concentrated in vacuo. The remaining light yellow foam is partitioned between 25 ml of water and 25 ml of ethyl acetate. The organic layer was washed with brine, dried and concentrated, and the residual light yellow oil was purified by FCC using B (60: 50: 1) as eluent to give 1.15 g of the title compound as a light yellow oil. TLC / System B, 50: 50: 1 / Rf b 0.26

By using the appropriate starting compound and following a known sequence of reactions, i.e. by following the sequence of Examples 3 and 5, the following compounds are prepared:

oC- (4-Amino-3,5-dichloro) -o 8- (N-benzyl-N- - {6- (3-) pyridinyl-3 / propoxy / hexyl J aminomatyl / methanol TLC / system B, 50: 50: 1 / Rf 0.28.

151,050 oC - (4-Amino-3,5-dichloro) - (N-benzyl-N- (2- (6-methylpyridinyl-2) ethoxy] hexyl] aminomethyl / methanol. TLC / system C, 92: 8: 1 / Rf = 0.17.

6- (4-Amino-3,5-dichlorophenyl) -o-(N-benzyl-N 6- (3- (pyridinyl-4) propoxy hexyl) aminomethyl) methanol. TLC / System B, 80: 20: 1 / Rf &lt; 0.04.

Example VI · / Z / - oe - (4-Amino-3,5-dichloro) - ot- (N-benzyl-N- 6 - [3- (pyridinyl-2) propen-2-yloxy] hexyl] Aminomethyl / methanol 0.6 g of 1-keto-1- (4-amino-3,5-dichlorophenyl) -2-bronioethane and 0.68 g of N- 6- (3-) pyridinyl-2 / propyne * 2 are used -yloxyHexylbenzylamine. Each of the two reaction steps is carried out for 16 hours, with 20 ml of methanol and 5 ml of THF as the reduction solvent used in the reduction process. After purification of the product by FCC using cyclohexane-ethyl ether / 1: 1 /, 0.7 g of the title compound is obtained as a light yellow oil. TLC / ethyl ether / Rf = 0.5

Example VII · O6- (4-Amino-3,5-dichlorophenyl) -o6- (N-benzyl-N- £ 6) 4- (3-hydroxypyridinyl-2) butoxy-7hexyljaminomethyl / methanol. 0.6 g of 1-keto-l (4-amino-3,5-dichlorophenyl) -2-bromoethane and 0.7 g of N- {6- (4-) 3-hydroxypyridinyl-2) butoxy I-hexyl-benzylamine are used. The first stage of the reaction was carried out in 18 hours and the second in 2.5 hours. After purification of the product by FCC method using the C (95: 5: 1) system as eluent, 0.6 g of the title compound was obtained in the form of a brown oil . TLC / system A, 80: 20: 1 / Rf = 0.25.

Example VIII OC - (4-Amino-3,5-dichlorophenyl) - ot- (N-benzyl-N-N-6 (2) pyridinyl-3) ethoxy-hexyl J amino-methyl / methanol. 98 g of 1-keto-1- (4-amino-3,5-dichlorophenyl) -2-bromoethane and 3 g of N6- (2- (pyridinyl-3-) ethoxy-7-hexyl Jbenzylamine. Each of the two reaction steps is carried out for 3 hours. Purification of the product by FCC using C (95: 5: 1 as eluent) gave 3 g of the title compound as a brown oil. TLC / C 95: 5: 1 system / Rf s 0.2.

Example IX. / E, Z / -4- / 3-Benzyloxy / pyridinyl-2 / buten-3-ol-1. A mixture of 3.9 g of 2-formyl-3-benzyloxypyridine, 8.38 g of / 3-hydroxypropyl / triphenylphosphonium bromide and 3.3 g of potassium carbonate in 30 ml of water-containing dioxane (0.27 ml) were heated to reflux for 18 hours. The cooled mixture was diluted with ether and filtered, and the filtrate was evaporated. The residue was purified by FCC using ether-hexane (3: 2) - ether as eluent to give 3.5 g of the title compound as a yellow oil. TLC / ether / Rf = 0.23.

Example 10 2- (4-) 6-Bromohexyloxy (butyl) - 3-hydroxypyridine. 1.5 g / Z / -2- / 4- (6-bromohexyloxy / buten-1-yl) J-3-benzyloxypyridine is hydrogenated in the presence of pre-reduced 10% palladium oxide on carbon / 300 mg 50% aqueous paste / w 15 ml of ethanol. The catalyst was filtered off using filter aid (hyflo) and the solvent was evaporated to give 1.18 g of the title compound as a yellow oil.

Elemental analysis for C ₁₅ H ₁₄ BrN0 ₂

Found: C 54.51 H 7.41 N 4.3 Br 23.83

Calculated: C 54.55 H 7.32 N 4.24 Br 24.19%

Example XI. N- 6- (-2-) pyridinyl-3 (ethoxy) - hexyl) benzylamine A mixture of 4 g of 2- (pyridinyl-3) ethanol, 23.78 g of 1,6-dibromohexane, 0.5 g of TAB and 50 ml of 2N sodium hydroxide are stirred vigorously for 3 hours. The mixture is diluted with 75 ml of water and then extracted with ethyl acetate and the combined organic extracts are washed with 150 ml of brine, dried and evaporated. The residual oil was purified by FCC using hexane - * hexane-ethyl acetate (19: 1) as eluent to give 6 g of 3- (2- (6-bromohexyloxy) ethyl pyridine. A solution of 5 g of this bromine compound and 15 ml of benzylamine was stirred at 140 ° C for 1 hour under nitrogen atmosphere. The cooled reaction mixture was partitioned between 150 ml of sodium bicarbonate solution and 50 ml of ethyl acetate. The organic layer was washed with 50 ml of brine, dried and concentrated to a yellow oil. Excess benzylamine was distilled and the remaining oil was purified by FCC using the system eluent. C / 95: 5: 1 /, giving 4 g of the title compound in the form of a yellow oil TLC / system A, 80: 20: 1 / Rf 0.5

151 050

Example 12 · 6- (2- (pyridinyl-2) / ethoxy _- 7-n-caproic acid. A solution of 1.0 g of 6- (2- (pyridinyl-2) ethoxy) hexanol and 5.90 g of pyridinium dichromate in 12 ml of DMF was stirred at room temperature for 24 hours. The solution is diluted with 100 ml of water and extracted with ether (2 x 100 ml). The combined organic extracts were washed with 100 ml of water, dried and evaporated in vacuo to give a colorless oil. The original aqueous phases are combined and re-extracted with dichloromethane (2 x 150 ml), washed with water (100 ml), dried and evaporated in vacuo to give a brown oil. The primary aqueous phases are buffered to pH 5.5 with a phosphate buffer and treated with solid NaCl. The saturated solution was extracted with dichloromethane (2 x 100 ml), washed with water (100 ml), dried and evaporated in vacuo to give a brown oil. The three oils are combined and purified by FCC using hexane-ether (1: 1) as eluent and then methanol and the resulting yellow oil is dissolved in 50 ml of dichloromethane and the solution is filtered. The filtrate was evaporated in vacuo to give 0.55 g of the title compound as a green oil. TLC (system A, 40: 10: 1), Rf = 0.6.

Example XIII. N- (- 2- (4-amino-3,5-dichlorophenyl) -2-hydroxyethyl) - 6 £ 2- (pyridinyl-2) ethoxy-7-n-capronamide, to a mixture of 0.5 under nitrogen atmosphere g 6- (2-pyridinyl-2) -ethoxy-7-n-caproic acid in 30 ml of acetronitrile are added in portions at room temperature 0.41 g of 1,1-carbonyldimidazole The mixture is stirred for 3 hours and then added dropwise thereto. At room temperature, a suspension of 0.46 of intermediate 2 in 10 ml of acetonitrile. The mixture was stirred for 2.5 hours at room temperature under nitrogen atmosphere. The solvent was evaporated in vacuo and the residue was purified by FCC using toluene-triethylamine-0.88 ammonia (95: 5: 1: 0- + 40: 10: 0: 1) as eluent to give 0.23 g of compound title in the form of a colorless oil. TLC (system A, 40: 10: 1) Rf &lt; 0.39.

Example XIV. Oc- (N-acatyl-N 6- (2-pyridinyl-2) ethoxy-7hexyl-aminomethyl) -acetate (4-amino-3,5-dichlorophenyl) methanol for a solution of 250 mg of acid - (4-amino-3, 5-dichlorophanyl (-? -? 2- (pyridinyl-2) (ethoxy) (hexylaminomethyl) methanol in 2 ml of pyridine, 132 mg of acetic anhydride in 2 ml of pyridine are added dropwise. The solution was stirred at room temperature overnight under nitrogen and stirred for 12 hours after adding 65 mg of acetic anhydride in pyridine. The solution was evaporated in vacuo and the residual oil was partitioned between 5 ml of water and 5 ml of ether. The aqueous layer was re-extracted with 5 mL of ether and the combined organic layers were dried and concentrated to give 190 mg of the title compound as a clear oil. TLC / system A, 80: 20: 1 / Rf = 0.5.

Example XV. 6- / 2- / Pyridinyl-2 / ethoxy-7-hexylamine · A solution of 2.00 g of N- {6- / * 2- / pyridinyl-2 / ethoxy-7-hexyl J benzylamine in 100 ml of ethanol is added to the pre-hydrated suspension 10 % palladium on carbon / 800 mg 50% aqueous paste / in 120 ml of ethanol and the mixture hydrogenated at room temperature under ordinary pressure. The catalyst is filtered off (hyflo) and the solvent is evaporated off in vacuo. The residual oil was purified by FCC using A (39: 10: 1.fwdarw.32: 17: 1) as the eluent to give 0.99 g of the title compound as a colorless oil. TLC / system A, 39: 10: 1 (R 5: 0.16).

Example XVI. 1-Keto-1- (4-amino-3,5-dichlorophenyl) -2- {6- [2- (pyridinyl-2-ethoxy]) hexylaminomethane. A mixture of 0.51 g of 1-keto-1- (4-amino-3,5-dichlorophenyl) -2-bromoethane, 0.40 g of 6- (~ 2- (pyridinyl-2) ethoxy-7hexylamine, 0.36 ml of DEA and 10 ml THF is left for 5 hours. The mixture is filtered and evaporated in vacuo. The residual resin was purified by FCC using toluene-ethanol (9: 1) as eluent to give 0.45 g of the title compound as a yellow gum. TLC / toluene-ethanol, 9: 1 / Rf = 0.45.

Example XVII. 5- (4-amino-3,5-dichlorophenyl-3- {6- [2-) pyridinyl-2-ethoxy] hexyl-2-ioxazolidinone. A solution of 100 mg of α - (4-amino-3,5-dichlorophenyl) - α - (aminomethyl) methanol and 38 mg of 1,1-carbonyldiimidazole in 20 ml of anhydrous THF was heated under nitrogen for 5 hours. The solvent was evaporated and the residue was purified by FCC using ethyl acetate as eluent to give 95 mg of the title compound as a light yellow oil. TLC / ethyl acetate / R fp 0.42.

Example XVIII. 1.13 g of m-chloroperbenzene acid is added in one portion to a solution of 1.0 g of 2- (6-bromo-hexyl) pyridine in 50 ml of dichloromethane. The solution is stirred at room temperature at overnight · Quench the reaction by adding 50 ml of 10% w / v sodium sulfite solution to the mixture · The organic layer is washed with 50 ml of 8% sodium bicarbonate · The organic layer is dried and evaporated to give 980 mg of the title compound as a light yellow oil which is then used without further purification. A portion (100 mg) of the product is purified by FCC using A / 80: 20: 1 / as eluent to give 20 mg of a light yellow oil.

TLC / system A, 80: 20: 1 / R _f> 0.48. .

E xample XIX. (E) - 1,2-ethyl ethylenedicarboxylate of oC- (4-amino-3,5-dichlorophenyl) o - {6- (2-) pyridinyl-2) ethoxy-7hexylaminomethyl methanol (4: 3). Solution 0.74 g of acid - (4-amino-3,5-dichlorophenyl) - OC - (aminomethyl) -2-bromoethane, 0.674 g of 2- (2- (6-brorahexyloxy) ethyl-7-pyridine N-oxide and 346 mg of DEA In 15 ml of DMF, it is heated at 80 ° C for 2 hours. The solvent was removed under high vacuum and the residue was purified by FCC using A (90: 10: 1) as eluent to give 488 mg of the free base title compound as a yellow oil. A sample (388 mg) of the free base was dissolved in 20 ml of methanol and a solution of 51 mg of fumaric acid in 5 ml of methanil is added to the solution. The solution is evaporated and the residue is triturated under 50 ml of ether to give 378 mg of the title compound as a white powder. TLC / system A, 80: 20: 1 / Rf = 0.35.

Example XX. 6 - (4-amino-3,5-dichlorophenyl) -o 6- (3- (pyridinyl-2) propoxy) (hexylaminomethyl) methanol 0.65 mg solution (Z) - (4-amino-3.5) -Dichlorophenyl) N-benzyl-N- {6- (3- (pyridinyl-2) propen-2-yloxy-7hexyl J-aminomethyl) methanol in 15 ml ethanol containing hydrochloric acid (27 mmol) is hydrogenated in the presence of 0.15 g of 10% palladium on carbon, then the mixture is filtered and evaporated. The residue is partitioned between 30 ml of 1M aqueous sodium hydrogen carbonate solution and 150 ml of ethyl acetate, and the organic phase is filtered and evaporated. The remaining brown gum was purified by FCC using A (93: 7: 1 85: 15: 1) as eluent to give 0.32 g of the title compound as a white solid, m.p. 38-41 ° C.

Elementary analysis for θ22 ^Η 31 ^^ 2 ^Ν 3θ2

Found: C 59.6 H 7.0 N 9.2

Calculated: C 60.0 H 7.1 N 9.5% (E) 1.2 / 2: 1 -Ethheldicarboxylate mp. 103-108 ° C, benzoate (1: 1) mp.

- 89 ° C and the hydrochloride salt has a mp. 67-72 ° C.

Example XXI. oC- (4-amino-3,5-dichlorophenyl) - 2- (pyridinyl-2) ethoxy- (hexylaminomethyl) methanol. 1.1 g of - (4-amino-3,5-dichlorophenyl) - (N-benzyl-N- (2- (pyridinyl-2) ethoxy-hexyl-aminomethyl) -methanol are hydrogenated in the presence of a pre-reduced 10% oxide palladium on charcoal / 200 mg 50% aqueous paste / in 10 ml of ethanol containing hydrochloric acid / 4 ml of concentrated HCl solution in ethanol, 1: 9 by volume / The catalyst is filtered off (hyflo), the solvent is evaporated and the remaining oil is separated between 25 mL of 8% sodium bicarbonate solution and 25 mL of ethyl acetate The organic layer was washed with 8% sodium bicarbonate solution, water and brine, dried and concentrated. The residual orange oil was purified by FCC using C / 95: 5: 1 as eluent. 90: 10: 1 /.

The resulting yellow oil was triturated with ether-hexane to give 280 mg of the title compound as a white solid, m.p. 94-96 ° C.

Elemental analysis for ^C 2 1 ^H 29 ^C 2 ^N 3 ° 2

Found: C 58.89 H 6.93 N 9.55 Cl 16.88

Calculated: C 59.16 H 6.86 N 9.86 Cl 16.63%

Example XXII. (E) - 1,2-ethylenedicarboxylate - (4-amino-3,5-dichlorophenyl) - oC - (6- (* 2- (6-methylpyridinyl-2) ethoxyhexylaminomethyl) methanol / 2: 1). Use is - (4-Amino-3,5-dichlorophenyl) - 6 - (N-benzyl-N-N-6 (2- (6-methylpyridinyl-2) (ethoxy) - hexyl) aminomethyl) methanol. by FCC using C (92: 8: 1) as eluent, 0.9 g of a light yellow oil was obtained. A solution of 870 mg of this oil and 126 g of fumaric acid in 10 ml of methanol is concentrated and the remaining oil is rubbed a few times.

151,050 times with ether to give 850 mg of the title compound as a white solid, m.p. 122-126 ° C.

Elemental analysis for / C _OO H_ Cl _o N_0_ / _o .CH 0.

ZZ dl £. d Z £. 4 4 4

Found: C 57.48 H 6.59 N 8.07 Cl 14.18

Calculated: C 57.83 H 6.67 N 8.43 Cl 14.23%

Example XXIII. (E) -Ethhene-1,2-dicarboxylate (4-amino-3,5-dichlorophenyl) - OC - 6 - (* 3- (pyridinyl-4) propoxy-7hexylarainomethyl methanol / 2: 1). Apply

690 ml of - (4-amino-3,5-dichlorophenyl) -6- (N-benzyl-N- (E3- (pyridinyl-4) propoxy I hexyl I aminomethyl) methanol. After concentrating the extracts, which were the solutions in ethyl acetate, 500 mg of red oil were obtained. A solution of the oil and 70 mg of fumaric acid in 5 ml of methanol was evaporated and the remaining yellow oil was triturated several times with ether to give 380 mg of the title compound as a cream solid, m.p. 112 - 115 C.

Elemental analysis for / ^C 22 ^H 31 ^C ^ 2 ^N 3 ° 2 ^ 2 * ^C 4 ^H 4 ° 4 ^{0.6 H} 2 °

Found: C 56.49 H 6.52 N 7.89

Calculated: C 56.60 H 6.78 N 8.25%

Example XXIV. (E) - 1,2-ethylenedicarboxylate - (4-amino-3,5-dichloro (enyl) -O? 6- (3-) pyridinyl-3- (propoxy)) hexylaminomethyl J methanol (2: 1). 1.5 g of 6- (4-amino-3,5-dichlorophenyl) -o-(N-benzyl-N- {δ- (3-) pyridinyl-3 (propoxy-hexyl) aminomethyl) methanol is hydrogenated in the presence of pre-reduced 10 % palladium on carbon / 300 mg 50% aqueous paste / in 20 ml of ethanol containing hydrochloric acid / 5 ml of concentrated HCl solution in CgHgOH 1: 9 by volume / · The catalyst is filtered off (hyflo) and the solvent is evaporated. The residual oil is partitioned between 50 ml of 8% sodium bicarbonate solution and 50 ml of ethyl acetate. The organic layer is washed with water and brine, dried, and concentrated. The residual oil was purified by FCC using a C (95: 5: 1 90: 10: 1) eluent to give 850 mg of a slightly colored oil. The oil in 10 ml of methanol is mixed with a solution of 115 mg of fumaric acid in 2 ml of methanol. The solvent was evaporated and the residue was triturated with anhydrous ether to give 770 mg of the title compound as a white powder. TLC / system A, 80: 20: 2 / Rf = 0.40.

Elemental analysis for / C22 ^H 3i ^C ^ 2 ^N 3 ° ^{4/2 eC} 4 ^H 4 ° 4

Found: C 57.53 H 6.75 N 8.12 Cl 13.90

Calculated: C 57.83 H 6.67 N 8.43 Cl 14.23%

Example XXV. oC - (4- (amino-3,5-dichlorophenyl) - 6 - / * 4- (3-hydroxypyridinyl-2) butoxy. (hexylaminomethyl) methanol 0.49 g of acid - (4-amino-3, 5-dichlorophenyl) -o (N-benzyl-N6- (4- (3-hydroxypyridinyl-2) butoxy (hexyl) -aminomethyl) methanol is hydrogenated in the presence of pre-reduced 10% palladium oxide on carbon / 100 mg 50 % aqueous paste / in 10 ml of ethanol containing hydrochloric acid / 1.6 ml of concentrated HCl and ethanol solution, 1: 9 by volume / · The catalyst is filtered off / hyflo /, the solvent is evaporated and the remaining oil is distributed between 15 ml of a 6% solution sodium bicarbonate and 15 ml of ethyl acetate. The organic layer is washed with 10 ml of 8% sodium bicarbonate solution, 10 ml of water and 10 ml of brine, dried and concentrated. The residual yellow oil was purified by FCC using C (95: 6: 1) as eluent and the resulting light yellow oil was triturated with ether to give 215 mg of the title compound as a white solid, m.p. 95-96 ° C.

Elemental analysis for C _o Η _Λ Cl N 0 23 33 233

Found: C 58.32 H 7.38 N 8.7 Cl 15.21

Calculated: C 58.72 H 7.07 N 8.93 Cl 15.07%

Fumaran / 2: 1 / has mp. 97-99 ° C.

Example XXVI. (E) - 1,2 oC - (4-amino-3,5-dichlorophenyl) -Ethheldicarboxylate) - OC 6 - (- 2-) (pyridinyl-3) ethoxy (hexyl) aminomethyl (methanol) (2: 1). In 30 ml of ethanol containing a solution of concentrated hydrochloric acid in ethanol / 4.1 ml, 1: 9 by volume / hydrogenated in the presence of pre-reduced 10% palladium oxide on carbon / 50% aqueous paste.

800 mg / 2.98 g acid - (4-amino-3,5-dichlorophenyl) - (phenylmethyl) 6 - / * 2- (pyridinyl-3 / ethoxy-hexyl) aminomethyl / methanol Catalyst drains off / hyflo / and filtrate

151,050 is evaporated. The residual oil is partitioned between 40 ml of 8% NaHCOg solution and 40 ml of ethyl acetate. The organic layer is washed with NaHCO3 solution (40 ml), water (40 ml) and brine (40 ml), and then concentrated. the oil was purified by FCC using the C (95: 5: 1) system as eluent. 1.58 g of a yellow oil was obtained. A solution of 1.57 g of this oil and 216 mg of fumaric acid in 10 ml of methanol was concentrated to give an oil which was triturated several times in ether. 1.47 g of the title compound were obtained as a white solid, m.p. 103-105 ° C.

Elemental analysis for

Found: Calculated: Example

C 57.26 C 57.03

XXVII, / C _o H Cl NO / .CHO '21 29 2 3 2'2 4 4 4

H 6.59 N 8.41 Cl 14.29

H 6.45 N 8.67 Cl 14.64%

O6- (4-amino-3,5-dichlorophenyl) triphenylacetate (- O6) 2- (pyridinyl-2) (ethoxy) (hexylaminomethyl) methanol (1: 1). To a warm solution of 100 mg of the compound of Example 21 in 2 ml of isopropanol is added a warm solution of 67.6 mg of triphenylacetic acid in 2 ml of isopropanol. The solution is stirred for 1 hour, allowing it to cool. The resulting solid was filtered off, washed with 1 ml of isopropanol and dried in vacuo at room temperature to give 126 mg of the title compound, mp. 125.5 - 126.5 ° C.

Elemental analysis for ^c 2 and ^H 29 ^Cl 2 ^N 3 ° 2 ^eC 20 ^H 16 ° 2 Found: C 68.55 H 6.3 N 5.75

Calculated: C 68.9 H 6.35 N 5.9%

By treating the o6- (4-amino-3,5-dichlorophenyl) -oC - ≤ 6- £ 2- (pyridinyl) ethoxy hexylaminomethyl methanol (free base) i.e. the compound of Example 21, the following salts are obtained with the appropriate acid in examples XXVIII - XXXVII.

Example XXVIII. Fumaran / 2: 1 /. Using 100 mg of free base and 13.6 mg of fumaric acid, 56.2 mg of the title fumarate is obtained with a mp of 116 - 116.5 ° C. NMR spectrum (DMSO (1.25 (4H, m, 2 CH ₂ ), 1.48 (4H, m, CH ₂ ), 2.65-2.9 (4H, m, 2 CH ₂ N), 2.95) 2H, t, CH _{2 of} pyridine), 3.38 (2H, t, CH ₂ O), 3.5-4.5 (br, NH, OH, CO ₂ H), 3.71 (2H, t, OH ₂ ) , 4.7 / 1H, dd,

CH), 5.48 (2H, s, NH ₂ ), 6.45 (1H, s, CH fumarate), 7.2-7.33 (4H, 2 CH aromat; H-3 and H-5 pyridine), 7.72 (1H, dt, H-4 pyridine), 8.5 (1H, d, H-6 pyridine).

Example XXIX. Succinate / 2: 1 /. Using 500 mg of the free base and 69.2 mg of succinic acid, 320 mg of the title succinate was obtained, m.p. 100-103 ° C.

Elemental analysis for / C H Cl N 0 / .C H 0 '21 29 2 3 2'2 4 6 4 Found: C. 56.5 H 6.7 N 8.45 Calculated: C. 56.9 H 6.65 N 8.65% Example XXX. 4-Chlorobenzoate (1: 1). Using 500 mg of the free base i

183 mg of 4-chlorobenzoic acid, 300 mg of the title 4-chlorobenzoate, m.p. 85-85 ° C.

Elemental analysis for CH Cl NO. CH C10 _n '21 29 2 3 2 7 5 2

Found: C 57.35 H 5.85 N 7.0

Calculated: C 57.7 H 5.9 N 7.2%

Example XXXI. Benzoate / 1: 1 /. Using 50 mg of the free base and 14.3 mg of benzoic acid, 31 mg of the title benzoate were obtained in the form of a white solid, m.p. 115-117 ° C.

Elemental analysis for ^C 21 ^H 29 ^C 2 ^N 3 ° 2 * ^C 7 ^H 8 ° 2

Found: C 61.0 H 6.5 N 7.45

Calculated: C 61.3 H 6.45 N 7.65%

Example XXXII. Benzenesulfonate / 1: 1 /. Using 50 mg of the free base and 19 mg of benzenesulfonic acid, 20 mg of the title benzenesulfonate were obtained as a brown-colored solid, mp 110-110.5 ° C. NMR Spectrum / DMSO / cf 1.25 / 4H, m, 2CH2 /, 1.4 - 1,7 / 4H, m, 2CH ₂ / 2.8 - 3.2 / 4H, m, 2CH _2/2 95 / 2H, t, CH ₂ pyridine / 3.38

151,050 (3Η, m, CH10, OH). 3.72 (2H, t, OCH ₂ ), 4.78 (1H, br, CH), 5.59 (2H, s, NH 6), 6.12 (1H, br.

NH), 7.2-7.4 (7H, m, 2CH aroma, H-3, H-5 pyridine, H-3, H-4, H-5 benzenesulfonate), 7.6 7.65 (2H, m, Hl and H-6 benzenesulphonate /, 7.72 / 1H, dt, H-4 of pyridine /, 8,3-8,7 / 1H, br, ^s ₃ 0 H /, 8.5 / 1 H, d, H-6 pyridine /.

Example XXXIII. Sulphate / 2: 3 / Using 200 mg of free base and 93.8 mg of sulfuric acid with a concentration of 98% by weight, 0.2 g of the title sulphate is obtained, m.p.

- 65 ° C / amorphous /

Elementary analysis for θ2ΐ ^ 29 ^^ 2 ^ 3θ2 ^^ 2θθ4 ^ 3

Found: C 44.15 H 5.9 N 6.95

Calculated: C 44.0 H 5.6 N 7.3%

Example XXXIV. 1-Hydroxynaphthalenecarboxylate-2 (1: 1). Using 500 mg of the free base and 220 mg of 1-hydroxynaphthalenecarboxylic acid-2 yields 700 mg of the title hydroxynaphthalene carboxylate as a light brown solid, m.p. 41 - 43 ° C / amorphous / ·

Elemental analysis for ^c 2 and ^H 29 ^Cl 2 ^N 3 ° 2 ^eC 11 ^H 8 ° 3

Found: C 72.3 H 6.1 N 6.5

Calculated: C 62.55 H 6.05 N 6.85%

Example XXXV. 4-Methylbenenenesulfonate (1: 1). Using 50 mg of the free base and 22 mg of p-toluenesulfonic acid, 60 mg of the title 4-methylbenzenesulfonate were obtained, mp 128-130 ° C. NMR Spectrum / DMSO / cf 1.25 / 4H, m, 2CH ₂ /, 1.4-1.7 / 4H, m, 2CH ₂ /, 2.31 / 3H, s, _CH3 /, 2.8 - 3.15 (4H, m, 2CH ₂ ), 2.95 (2H, t, CH _{2 of} pyridine), 3.38 (3H, m, CH ₂ O, OH), 3.71 (2H, t, OCH ₂ /, 4.75 (1H, d, H), 5.59 (2H). s, NH ₂ ), 6.12 (1H, br, NH), 7.13 (2H, d, H-3 and H-5 benzenesulfonate), 7.2-7.35 (4H, m, 2CH aromatic, H-3 and H-5 of pyridine /, 7.5 (2H, d, H-2 and H-6 of the benzenesulfonate), 7.72 (1H, dt, H-4 of pyridine), 8.2-8.7) 1H, br, S0 ₃ H /, 8.5 / 1 H, d, H-6 of pyridine /.

Example XXXVI. oce, octo-diphenylacetate / 1: 1 /. Using 50 mg of the free base and 25 mg of α, 6-diphenylacetic acid, 46 mg of the title OD, 8-diphenylacetate were obtained as a cream solid, mp 105-107 ° C. NMR Spectrum / DMSO / (1.24 J / 4H, m, _CH2 /, 1.45 / 4H, m, 2CH ₂ / 2,6 - 2,9 / 4H, m, 2CH ₂ /, 2.95 (2H, t, CH _{2 of} pyridine), 3.37 (2H, t, CH ₂ O), 3.71 (2H, t, OCH ₂ ), 4.67 (1H, dd, CH), 4.9 (1H) s, CH diphenylacetate /, 5.45 (2H, s, NH ₂ ),

7.15-7.4 (14H, dt, H-4 pyridine), 8.49 (1H, d, H-6 pyridine).

Example XXXVII. Adypinian / 1: 1 /. Using 100 mg of free base and 17.1 mg of adipic acid, 54 mg of the title adipate are obtained, m.p. 94-96 ° C.

Elemental analysis for / C ₂₁ ^H 29 ^Cl 2 ^N 3 ° 2/2 ° ^C 6 ^H 10 ° 4

Found: C 57.25 H 7.05 N 8.35

Calculated: C 57.7 H 6.85 N 8.4%

Example XXXVIII. 6 - (4-amino-3,5-dichlorophenyl) - {&lt; 2 - (pyridinyl 2) ethoxy-7-hexylaminoethyl} methanol. A solution of 0.166 g of N - (2-04-amino-3,5-dichlorophenyl) -2-hydroxyethyl) -6- (* 2- (pyridinyl-2) ethoxy-n-capronamide in 5 ml of benzene is added dropwise to the mixture under stirring. a suspension of 0.065 g of aluminum lithium hydride in 5 ml of ether at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature for 3 days under nitrogen atmosphere, then the reaction was carefully quenched by adding 0.5 ml of water successively.

0.5 ml of 2N sodium hydroxide solution and 2 ml of water. The mixture is diluted with 50 ml of ether, filtered (hyflo), quenched with additional dichloromethane and the filtrate evaporated in vacuo. The resulting oil was purified by FCC using C (95: 5: 1 to 90: 10: 1) as eluent to give a colorless oil. Trituration of the oil with ether / hexane gave 67 mg of a white solid. This substance is further purified on a silica column (Merck 9385) and a column containing 10 ml silica (Merck 9385), deactivated triethylamine, using as eluent the system C / 98: 2: 1 -> 95: 5: 1 / and toluenmethanol respectively / 98: 2 /, giving a colorless oil, identified as the title compound · TLC / system A, 39: 10: 1 / R _f - 0.44.

151 050

Example XXXIX - (4-amino-3,5-dichlorophenyl) - O 6 - {6 - (N-acetyl-N) - {6 - (N-acetyl-2) / ethoxy / hexylaminomethyl J methanol - {6 (2-) pyridinyl-2) ethoxy (hexyl) aminomethyl (4-amino-3,5-dichlorophenyl) methanol in 5 ml sodium hydroxide solution and 5 ml ethanol are stirred at room temperature for 18 hours The mixture was refluxed for 20 hours, cooled, evaporated in vacuo, and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were dried and concentrated and the residual yellow oil was triturated with a mixture of ether and hexane to give 80 mg of the title compound, m.p.

- 95 ° C. TLC / system A, 80: 20: 1 / R _f = 0.44.

Example XL. oC- (4-amino-3,5-dichlorophenyl) - f 6- (2-) pyridinyl-2) ethoxy (hexylaminomethyl) methanol. 0.56 g of oC-keto- (4-amino-3,5-dichlorophenyl) acetaldehyde are dissolved in 10 ml of benzene and the solution is heated to reflux for 1 hour using a Dean-Stark trap. The solution is cooled, evaporated in vacuo and the residue is dissolved in 10 ml of methanol. While the solution is stirred at a temperature of 0-5 ° C, 0.38 g of sodium borohydride is added thereto over 0.5 hours. The solution was left overnight and then evaporated. The residue is partitioned between 50 ml of water containing 2N sodium hydroxide (4 ml) and 60 ml of ethyl acetate. The organic phase is dried and evaporated in vacuo and the residue is purified by FCC using C (90: 10: 1) as eluent. to give a resin · After trituration with hexane, 85 g of the title compound are obtained as a colorless powder with a mp 93-96 ° C. TLC / system A, 39: 10: 1 (Rf? 0.44).

Example XLI. Ethoxy (4-amino-3,5-dichlorophenyl) -o6- "2- (pyridinyl-2) ethoxy (hexylaminomethyl) methanol. A solution of 100 mg of methanol 1-oxide O6 - (4-amino-3,5-dichlorophenyl) - oC -? 6- (2-) pyridinyl-2 / ethoxy / hexylaminomethyl J methanol in methanol is hydrogenated in the presence of about 100 mg of nickel Raney. The reaction is stopped after uptake of 5 ml of hydrogen. The catalyst was filtered off (hyflo) and the filtrate was evaporated to give a light pink gum. Purification by FCC using A (80: 20: 1) as eluent gave 20 mg of the title compound as a white, crystalline solid, mp 94-95 ° C. TLC / system A, 39: 10: 1 / R _f = 0.44.

Example XLII. 8 - (4-amino-3,5-dichlorophenyl) - O 6 - {6- (2-) pyridinyl-2) ethoxy (hexylaminomethyl) methanol. Stirring at 0 - 5 C solution of 0.44 g of 1-oxo-l- / 4-amino-3,5-dwuchlorof enyl / -2 ° C 6 / ^- 2- / pyridinyl-ethoxy / hexylamino-ethane in 7 ml methanol is added portionwise over 5 minutes, 0.16 g of sodium borohydride. After 1.5 hours, the solution was evaporated in vacuo and the residue was partitioned between 60 ml of water and 100 ml of ethyl acetate. The organic phase is dried and evaporated in vacuo and the residual resin is purified by FCC using the C (90: 10: 1) system as eluent. Triturate the product with 2 ml of hexane to give 47 mg of the title compound as a colorless powder, mp 94.5-96.5 ° C.

TLC / system A, 39: 10: 1 / R _f = 0.44.

Example XLIII. 8- (4-amino-3,5-dichlorophenyl) -Oh - 6- / 2- / pyridinyl-2 / ethoxy / hexylaminomethyl} methanol · Solution 80 mg 5- (4-amino-3,5-dichlorophenyl) -3 - {6 / ^- 2- / 2-pyridinyl / ethoxy / hexyl] 2-oxazolidinone in 1 ml of 2N hydrochloric acid and 5 mL of THF was heated at 80 ° C for 2 hours. The solvent was evaporated and the free residue was extracted with ethyl acetate (2 x 25 ml). The aqueous layer was basified to pH 10 with 2N sodium hydroxide solution and extracted with ethyl acetate (3 x 25 ml). The combined extracts were dried and evaporated to give 70 mg of a light yellow resin. Crystallization from a mixture of ethyl acetate and n-hexane gave the title compound as a white crystalline solid, mp 97.5-100 ° C. TLC / A system 39: 10: 1 / R _f - 0.44.

Claims (3)

Patent claims 1. A process for preparing a dichloroaniline of Formula 1, wherein X represents a group - / CH _2/4 - or - / CH _2/2 C 'C, Y is -CH ₂ "- / CH _2/2 - or- / CH _2/3 -, 151 050 AO, ^R is a hydrogen atom, R is a hydrogen atom or a methyl group, and Py is a pyridyl group linked at the 2, 3 or 4 position to the rest of the molecule and optionally having a substituent such as hydroxyl or methyl as well as physiologically acceptable salts and solvates of these compounds, characterized in that the compound of general is reduced 1 2 of the formula Z, where X ¹ is the group -CH / OH / - or the group - (C = O) -, X is the group of the formula -CH NR ₉ -, wherein R is a hydrogen atom, a benzyl group, a benzhydryl group or a 2 3 OO-methylbenzyl, or X is -CH = N or -CONH-, X is a group of formula -Cr! R ² X-, wherein R ^1, R ² and X are as defined above, a group of formula -C0X-, wherein X is as defined above, or a group of the formula -CR R ⁸ -, wherein R and R ² are as defined above and X ⁵ represents a C 1-6 alkenylene or C 1-4 alkynylene group, or the group -X ² -X ³ - represents a group of the formula -CH ² N = CR ² X, in which R ² 'and X are above as indicated, X ⁴ is a group of the formula -NHR ⁸ , in which R ⁶ is a hydrogen atom, a benzyl group, an o-methylbenzyl group, a diphenylmethyl group, a triphenylmethyl group, an acetyl group, a trichloroacetyl group or a trifluoroacetyl group, or X ⁴ is a group nitro, Y * is -CH 2 - / CH _2/2 - - / CH ₂ / g- C ₂ -C ₃ alkenyl or C ₂ -C ₃ alkynyl, and Py * has the same meaning as Py or is an N-oxidopyridyl group , optionally substituted with hydroxy or methyl, at least one of X ¹ , X ² , X ³ and X ⁴ being a reducible group and / or Y * being a reducible group and / or Py * having a reducible group, whereby any protective group present or any protective groups present is removed and the resulting compound is optionally converted to a physiologically acceptable salt or solvate. The method according to claim 1, characterized in that in the preparation of oC- (4-amino-3,5-dichlorophenyl) - oC- 6- (2-) pyridinyl-2- (ethoxy) (hexylaminomethyl) methanol and its physiological acceptable salts and solvates are reduced to a compound of general formula 2, in which X ¹ is -CH / OH) - or -C f = O / -, X ² is a group of formula -CH 2 R ³ , 3 2 3 wherein ⁿ oz ACZA hydrogen atom or a benzyl group, or X is -CH = N-, X is a group - / CH2 /, _- "CO / CH ^ / ^ -, X ⁴ is a group Η2Ν-. Y * is a group - / CH _2/2 "and Py * is pyridyl or N-oksydopirydylową, wherein at least one of X ^1, X ^ and χ3 is a group which can be reduction and / or Py * contains a reducible followed by removal of any protecting group present and the resulting compound optionally converted to a physiologically acceptable salt or solvate. , 1 151 050 Η, Ν C11HCH2NHCXCH2OCH ₂ Y- Py 'R ² Formula 1 Cl Cl ID .1 _{4 X} 4 '\ yx'-X ² -X ₂ CHpCH ^L Y ^L Py • Pattern 2 Cl x ' Cl C0CH ₂ Hal Formula 3 R ⁹ NHCXCH ₂ OCH ₂ Y'- Py ¹ R ² Formula 4 151 050 Cl X ⁴ - ^ yC0CH0 ^Cl - R Formula 5 Qj ^χ4 X ^Lch 2NHR3 θΐ Formula 6 P ^_y -Y'CH ₂ OCH ₂ XCO ₂ H Formula 7 LCHXCH2OCH ₂ Y'- Py ' R ^z Formula 8 Publishing House of IIP RP. Circulation 100 copies. Price 1500 PLN